Platelet secretion: From haemostasis to wound healing and beyond

Abstract

Upon activation, platelets secrete more than 300 active substances from their intracellular granules. Platelet dense granule components, such as ADP and polyphosphates, contribute to haemostasis and coagulation, but also play a role in cancer metastasis. α-Granules contain multiple cytokines, mitogens, pro- and anti-inflammatory factors and other bioactive molecules that are essential regulators in the complex microenvironment of the growing thrombus but also contribute to a number of disease processes. Our understanding of the molecular mechanisms of secretion and the genetic regulation of granule biogenesis still remains incomplete. In this review we summarise our current understanding of the roles of platelet secretion in health and disease, and discuss some of the hypotheses that may explain how platelets may control the release of its many secreted components in a context-specific manner, to allow platelets to play multiple roles in health and disease.

Keywords: Cancer metastasis; Haemostasis; Inflammation; Platelets; SNARE proteins; Secretion; Thrombosis.

Fig. 1

Schematic of platelet activation cascade leading to the haemostatic plug formation. Platelet adhesion to ECM components via integrin or GPVI receptors or activation with soluble agonists via GPCR receptors leads to platelet activation. One of the hallmarks of platelet activation is secretion of bioactive molecules from dense and α-granules, which can then act to activate further platelets, as well as in an autocrine manner to drive positive feedback cascade. ‘Inside-out’ signalling initiated by platelet activation also causes activation of integrin αIIbβ3. Platelets also undergo a dramatic shape change, increasing their surface area available for adhesion to ECM and to one another. Activated integrin αIIbβ3 and fibrin contribute to formation of the initial aggregate or platelet plug. Platelets also expose PS providing attachment sites for coagulation factors. The coagulation cascade contributes to the stabilisation of the thrombus.

Fig. 2

Currently accepted model of platelet secretion. Three SNARE proteins: transmembrane VAMP8, with some additional VAMP2 and VAMP3 contribution (blue), and membrane-anchored STX11 (green) and SNAP23 (red) form the core SNARE complex in platelet secretion. MUNC13-4 and MUNC18-2 (purple) are also essential for secretion, although their exact mechanism of action is not fully understood. RAB27b, along with other small GTPases (orange) is also implicated.

Fig. 3

Simplified illustration of events leading to vessel injury repair. Following the initial platelet plug formation, coagulation cascade activation results in production of fibrin that reinforces the thrombus. Then leukocyte recruitment from the blood leads to an inflammatory response and antimicrobial response. Finally, wound healing and vessel wall remodelling lead to restoration of the continuity of the endothelium. Secretion of the 300 + bioactive substances from platelet intracellular stores is likely to be a major driver of these events.

Fig. 4

Summary of some of the platelet granule cargoes and their functional classification. α-Granules (left hand side) contain cargoes with often opposing actions (e.g. angiogenesis and coagulation-related factors), hence a mechanism(s) ensuring tight spatial and temporal regulation of secretion is likely to be in place to allow platelets to exert their many functions. Some of the physiological (green) and pathological (red) processes that are now known to be affected by platelet secretome are also listed (amber indicates both depending on the scenario). Many of those physiological and pathological processes can be affected by a combination of factors. It should be noted that although functions are assigned to each cargo here, many cargoes have multiple roles, while the roles of others still have not been fully elucidated.